Académie royale de Médecine de Belgique

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Lucienne Chatenoud (France)

(Séance du 28 octobre 2000)

MECHANISMS OF IMMUNE TOLERANCE TO ALLOGRAFTS : ANTI-T CELL ANTIBODIES ARE UNIQUE TOLERANCE PROMOTING TOOLS         

par Mme L. CHATENOUD (Inserm – Hôpital Necker – Paris).  

Organ and bone marrow transplantation represent the only therapeutic possibility for a variety if life threatening conditions.  The immune response to alloantigens is mediated by functionally distinct monocyte and lymphocyte subsets (macrophages, dendritic cells, B cells, effector and immunoregulatory T cells) that interact through an intricate network of membrane receptors and soluble mediators.  Current therapeutic approaches are essentially based on non-specific immunosupressants that are small molecules (corticosteroids, azathioprine, mycophenolic acid, calcineurin inhitibors), whose activities are targetd to intracellular processes.  The major drawback of these non-antigen specific agents is their relative ineffectiveness over the long term with the likely risk of recurrence of the pathogenic immune process once the drug is withdrawn, so necessitating indefinite drug administration with the attendant infectious and tumorigenic risks linked to long term immunosuppression. One major goal in clinical transplantation is to establish immunointervention strategies in which the immune system can be selectively immune-suppressed just to those antigens unique to the target tissue.  Operationally, this means the establishment of immunological tolerance in a mature immune system that may be defined as a state of durable antigen specific unresponsiveness in the absence of generalized immunosuppression.

A long-held dogma was that immune tolerance could only be achieved through central deletion of potentially reactive T and B lymphocytes in their site of origin that is the thymus or the bone marrow respectively.  However, it is now extensively documented that even in the case of physiological tolerance (i.e. immune tolerance to self antigens) deletion mechanisms ensure the elimination of most but not all autoreactive cells.  Thus autoreactive lymphocytes migrate into the periphery and are under the control of tolerance immune mechanisms some of which are clearly non-deletional and include indifference, anergy or immunoregulation.

In terms of therapeutic strategies almost 20 years of experience in using immunosuppressive monoclonal antibodies for studies mainly in experimental and clinical transplantation, but also in autoimmunity, has clearly demonstrated the existence of therapeutic activities not shared by conventional chemical immunosuppressants.  Antibodies to CD3 have been remarkably efficacious in reversing severe acute allograft rejection, a clinical situation in which only high dose steroids and polyclonal antilymphocyte antibodies have similar efficacy.  More importantly, antibodies or genetically engineered molecules to distinct T cell receptors (CD4, CD4+CD8, CD28/CTLA4IG, CD40/CD40Ligand, adhesins) can promote transplantation tolerance in the adult.  Thus, despite the different problems surrounding their production and preclinical/clinical development (i.e. high cost, side effects namely, acute cytokine-related syndrome, sensitization…), continued effort in pursuing the study of therapeutic monoclonals appears worthwhile.

From a more fundamental point of view, understanding the molecular basis of the tolerogenic properties of monoclonal antibodies would clear the way for development of more easily accessible therapeutic strategies i.e. simple chemicals or recombinant receptor agonist and/or antagonist ligands that would mimic the desired therapeutic effect.

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